Five multivariate Duchenne muscular dystrophy progression models bridging six-minute walk distance and MRI relaxometry of leg muscles

Abstract

The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T₂) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T₂. Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T₂ of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T₂ model variables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T₂. Sigmoid I_max and E_max models best captured the profiles of 6MWD and MRI-T₂ over age. Steroid use, baseline 6MWD, and baseline MRI-T₂ were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T₂ is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T₂ successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T₂, supporting the use of MRI-T₂. The developed models will guide drug developers in using the MRI-T₂ to most efficient use in DMD clinical trials.

Keywords: Clinical trial simulation; Disease progression; Drug development tools; Duchenne muscular dystrophy; Magnetic resonance imaging; Model-informed drug development; Quantitative imaging biomarkers; Rare diseases; Six-minute walk distance.